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Hepatitis B or Hepatitis C and HIV-infection Diagnosis/Care/Treatment
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Journal of Hepatology April 2005
Robert Thimme, Hans Christian Spangenberg, Hubert E. Blum*
Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, D-79016 Freiburg, Germany
Article Outline
1. Introduction
2. HBV--HIV coinfection
2.1. Natural history
2.2. Diagnosis and management
2.3. Treatment
3. HCV--HIV coinfection
3.1. Natural course
3.2. Diagnosis and management
3.3. Treatment
4. Summary and perspectives
References
"...there is consensus that HIV infection accelerates HCV related liver disease, especially when immunodeficiency progresses. Thus, with increasing survival of HIV-infected patients due to HAART and prophylaxis of opportunistic infections, HCV related morbidity and mortality increases and has already become a major cause of hospital admissions and death among HIV-infected patients...
... All patients with HIV infection should be screened for HBV infection... Up to 80% of HIV-infected patients have been exposed to HBV and up to 10% have chronic hepatitis B... The optimal screening strategy has not yet been defined but is usually based on the determination of HBsAg (hepatitis B surface antigen) and anti-HBs... Despite the initially mild clinical course, the HBV-related liver disease in HIV-infected patients is more progressive,... The Multicenter Cohort Study, for example, has reported a liver-related mortality rate of 14.2 per 1000 person years in HBV--HIV coinfected men compared to 0.8 per 1000 person years in men infected with HBV only...All HIV infected individuals should be screened for HCV infection... loss of HCV antibodies (anti-HCV) can occur in a subset of HCV--HIV coinfected patients and may be associated with low CD4 counts. Therefore, in anti-HCV negative HIV-infected persons with unexplained liver disease serum HCV RNA should be determined... A liver biopsy should be considered before therapy to assess the grade and stage of the chronic hepatitis C. This information may be helpful for the decision to treat or not to treat the HCV infection, to estimate prognosis and to rule out other coexisting causes underlying the liver disease, such as drug-induced liver injury, iron overload and others...
...liver disease and in particular hepatitis C has emerged as one of the most important causes of morbidity and mortality in HIV-infected patients... HIV coinfection has been associated with higher HCV RNA levels, a more rapid progression of the chronic liver disease and a higher incidence of cirrhosis and HCC (liver cancer)... persons with HCV--HIV coinfection are three times more likely to develop cirrhosis or advanced liver disease than patients infected with HCV only...prognostic factors include gender, duration of HCV infection and alcohol consumption...HIV infection may also accelerate the development of HCC in patients with chronic hepatitis C since HCC occurs...
... HAART may positively affect the natural course of HCV infection... These benefits seem to outweigh the increased risk of hepatotoxicity of HAART... HAART should be offered to HCV--HIV coinfected patients...
... Very little information with respect to the specific mechanisms by which HIV accelerates the course of HCV infection is currently available... data suggest that accelerated progression of liver disease in HCV--HIV coinfected patients is linked to the loss of CD4+ T cells...
... Treatment is recommended for persons with chronic hepatitis C who are at greatest risk for progression to cirrhosis, characterized by serum HCV RNA positivity and histological findings of active inflammation (grade) and advanced fibrosis (stage)...
... HCV treatment goals are elimination of HCV infection, risk reduction for liver failure and as well as better tolerance of anti-HIV therapy, such as HAART. Thus, patients with adequately controlled HIV disease, compensated liver disease and evidence of chronic hepatitis on liver biopsy should be evaluated for therapy...
...treatment study results in coinfected patients together with the poor prognosis for HCV--HIV coinfected patients justify broad use of anti-viral therapy in these patients..."
1. Introduction
Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is common among patients infected with the human immunodeficiency virus (HIV), due to the common epidemilogical risks. Recommendations for the management of patients with chronic hepatitis B and C, although continuously evolving, have recently been formulated in the US and Europe [1--7]. However, for special patient groups treatment modalities are less well defined and therapeutic options often have to be evaluated on an individual basis. These include among others patients with advanced liver disease or decompensated liver cirrhosis, transplant recipients, patients with asymptomatic hepatitis B or hepatitis C with normal ALT levels undergoing immunosuppressive therapy, and patients coinfected with HBV or HBV and hepatitis delta virus (HDV) and HIV or HCV and HIV, HBV, HCV and HIV or HBV, HDV, HCV and HIV. In the following, we will briefly review the natural course, management and current treatment modalities for patients coinfected with HBV or HCV and HIV.
2. HBV--HIV coinfection
HBV is a non-cytopathic, hepatotropic virus with more than 350 million infected individuals worldwide 8. It is the leading cause of chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC) and is associated with significant morbidity and mortality 9. HIV and HBV have common routes of transmission. Up to 80% of HIV-infected patients have been exposed to HBV and up to 10% have chronic hepatitis B [10,11]. Despite an effective vaccine against HBV, which is recommended for individuals at high risk of exposure, there is a rising incidence of acute HBV infection in HIV-infected individuals.
2.1. Natural history
In otherwise healthy adults, acute HBV infection is eliminated in 90--95%, associated with a broad and multispecific cellular immune response and the loss of hepatitis B surface antigen (HBsAg) and seroconversion to anti-HBs antibodies that convey protection against reinfection 9. In HIV-infected patients, however, the clearance rates of HBsAg and hepatitis B e antigen (HBeAg) are reduced compared to individuals without HIV infection, possibly related to the degree of immunosuppression [12,13]. This phenomenon can be explained by the impaired cellular immune responses in HIV infection that lead to a higher chronicity rate of HBV. However, due to the weak immune responses against HBV, the clinical course of HBV infection (ALT elevations) is usually benign and frequently asymptomatic, although HBV replication is enhanced. Despite the initially mild clinical course, the HBV-related liver disease in HIV-infected patients is more progressive, including the development of cirrhosis and its complications, compared to patients with HBV infection only and thus contributes significantly to the morbidity and mortality of HIV-infected patients [13--16]. The increase in liver-related mortality appears to be particularly pronounced since the introduction of highly active anti-retroviral therapy (HAART). The Multicenter Cohort Study, for example, has reported a liver-related mortality rate of 14.2 per 1000 person years in HBV--HIV coinfected men compared to 0.8 per 1000 person years in men infected with HBV only 17. Interestingly, in this study the individuals with lower CD4 T cells were at greater risk. The pathophysiologic basis for this observation is unclear at present, but may involve increased liver injury as a consequence of immune restoration under HAART, hepatotoxicity of certain anti-HIV drugs and the longer life expectancy of patients treated with HAART.
2.2. Diagnosis and management
All patients with HIV infection should be screened for HBV infection. The optimal screening strategy has not yet been defined but is usually based on the determination of HBsAg and anti-HBs. In the case that both markers are negative, an active hepatitis B vaccine should be administered. Vaccination is safe in HIV infected patients, but a higher proportion of these patients may not develop protective immunity (30% primary non-response to HBV vaccine in HIV infected individuals versus 2.5% in healthy individuals) or are more likely to lose their immunity over time [18,19]. Testing for HBsAg and anti-HBs, however, will not identify patients with occult HBV infection who are typically serologically positive for anti-HBc only. In this situation anti-HBc and serum HBV DNA should be determined. Table 1 gives an overview of the different serological patterns after HBV infection.
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2.3. Treatment
The aim of HBV treatment is to reduce liver inflammation, to prevent progression of disease towards liver cirrhosis and HCC and ideally to eradicate HBV infection. The AASLD recommends treatment of HBV in patients without HIV infection in HBeAg positive chronic hepatitis with evidence of liver injury (ALT>2×upper limit of or necroinflammation on biopsy) and in HBeAg negative chronic hepatitis B with HBV DNA levels >105copies/ml 20. The same criteria can be applied to patients coinfected with HIV, taking into account the stage of the HIV disease. A liver biopsy may be helpful for the decision to treat or not to treat the HBV infection. A delayed initiation of therapy may reduce HAART toxicity or prevent viral resistance in HBV--HIV coinfected individuals. Currently there are three commercially available treatment modalities for chronic HBV infection: interferon alfa (IFNα), lamivudine and adefovir.
IFNα is usually given as subcutaneous injection of 5 million units daily or 10 million units three times per week 20. It is a cytokine with anti-viral and immunomodulatory effects. Its highest effectiveness has been demonstrated in patients with HBeAg, high ALT levels (>2×upper limit of normal) and lower HBV DNA levels (<2.8×107copies/ml) [21,22]. Based on these selection criteria, IFNα treatment for 16 weeks results in sustained response rate of approx. 33% 23. With respect to HBV therapy in HBV--HIV coinfected patients, the limited information currently available indicates that the response rate decreased in coinfection as compared to HBV infection only. In the above mentioned meta-analysis of randomized trials with a total of 837 HBV infected persons 55 individuals were coinfected with HIV and showed a significantly lower seroconversion rate 23. However, most of the studies were not randomized according to the HIV status and did not take the CD4 T cell count or the ALT levels into account. Trials performed in the pre-HAART era also showed reduced sustained response rates in coinfected patients [23--26]. In summary, IFNα treatment in HBV--HIV coinfection may be an option in selected patients as described above with good immune function (CD4 cell count >500). Furthermore, therapy with pegylated (PEG) IFNα may be more efficacious in treating HBV in HIV positive individuals. However, randomized controlled studies are needed to answer this important question.
The nucleos(t)ide analogues lamivudine (LAM) and adefovir (ADV) are commercially available for the treatment of chronic HBV infection. LAM, which has excellent anti-viral activity against HIV and HBV suppresses viral replication of both viruses and results in improvement of the histological activity index (HAI). In HIV infection LAM is administered at a dose of 150mg twice as a component of HAART regimen while in patients with HBV infection only the dose 100mg once a day. In studies of HBV--HIV coinfected patients, HBeAg seroconversion rates of 22--28% can be achieved, similar to patients with HBV infection only [27,28]. However, long-term treatment with LAM is limited by the development of LAM-resistant mutants that usually have mutations in the YMDD motif of the catalytic unit of the polymerase gene. Resistance seems to emerge in HBV--HIV infected patients more rapidly than in HIV-negative patients. Rates of LAM resistance as high as 50% at 2 and 90% at 4 years have been reported 16. Flares in liver disease usually indicate the development of LAM resistance. LAM therapy should not be stopped, however, in these cases because severe recurrent hepatitis with even fatal complications may evolve 29. In this situation a therapy with the nucleotide analogue ADV should be instituted that efficiently suppresses HBV replication and appears to even decrease the pool of covalently closed circular (ccc) HBV DNA [30,31]. It is unclear whether ADV should be added to LAM therapy or given sequentially. At a dose of 10mg/d ADV is well tolerated and does not affect HIV RNA levels or CD4+ T cell counts. Interestingly, there is a transient increase in serum ALT levels by week 8--24 occurs in a number of patients treated with ADV, possibly related to immune reconstitution under effective anti-viral therapy. To date, ADV resistant mutants appear to be rather uncommon (1.6% after 96 weeks of treatment) 32. Tenofovir disoproxil fumarate (TDF), another nucleotide analogue with activity against HIV at a dose of 300mg/d, has recently emerged as an attractive alternative for HIV-infected patients with LAM-resistant HBV infection [33,34]. Several pilot studies have shown excellent effectiveness against HBV. Based on recent data, TDF may become an alternative to ADV for the treatment of patients with LAM-resistant HBV infection 35. To date, however, TDF has been licensed for the treatment of HIV infection only.
Due to the limited data on the treatment of HBV--HIV coinfection, no evidence based guidelines exist. In principle, treatment decision have to be made on an individual basis and should consider the aspects guiding the treatment decisions mentioned above 36.
Liver transplantation in patients with advanced liver cirrhosis and/or HCC in HBV--HIV coinfection might be an option for selected patients. Recent reports indicate in a limited number of patients that the outcome of liver transplantation in selected patients with HIV infection may be as good as in those without HIV infection 37.
3. HCV--HIV coinfection
Coinfection with HIV and HCV is common in Europe and the USA, affecting approximately 25% of HIV-infected individuals and 5--10% of HCV-infected patients [38--40]. The high prevalence of HCV--HIV coinfections is attributed to common risk factors for transmission, i.e. blood and blood products. However, since HCV is about 10 times more infectious than HIV, coinfection is more common in patients with high volume exposure to blood. Thus, the prevalence of HCV coinfection in HIV-infected persons depends largely on the mode of HIV transmission. It is high in patients after parenteral transmission such as injecting drug use (91%) or transfusion of blood or blood products (71%), and comparatively low after sexually transmitted HIV infection (7.3%) 41. HCV is transmitted to 2--5% of infants born to HCV-infected mothers and the incidence increases if the mother is coinfected with HIV 42.
Since the introduction of HAART, the incidence of most opportunistic infections and overall mortality have sharply declined in HIV-infected patients 43. At the same time, liver disease and in particular hepatitis C has emerged as one of the most important causes of morbidity and mortality in these patients 44.
3.1. Natural course
HIV infection appears to adversely affect the outcome of acute and chronic HCV infection. Indeed, spontaneous recovery from HCV infection occurs in only 5--10% of HIV infected patients and even less in those with low CD4+ T cell counts. By comparison, HCV can be cleared in up to 35% in HIV-uninfected patients [2,38,45,46]. In persons with chronic HCV infection, HIV coinfection has been associated with higher HCV RNA levels, a more rapid progression of the chronic liver disease and a higher incidence of cirrhosis and HCC [16,25,47--56]. Indeed, persons with HCV--HIV coinfection are three times more likely to develop cirrhosis or advanced liver disease than patients infected with HCV only 48. In the UK National Haemophilia Register men with haemophilia exposed to HCV and HIV were 4.6-fold more likely to die from liver disease than HIV infected men without HCV infection 49. The level of CD4 immunosuppression has emerged as one of the most important determinants of progression to liver disease 57. Additional prognostic factors include gender, duration of HCV infection and alcohol consumption. HIV infection may also accelerate the development of HCC in patients with chronic hepatitis C since HCC occurs at a younger age in coinfected patients compared with those infected with HCV only 55. Taken together, there is consensus that HIV infection accelerates HCV related liver disease, especially when immunodeficiency progresses. Thus, with increasing survival of HIV-infected patients due to HAART and prophylaxis of opportunistic infections, HCV related morbidity and mortality increases and has already become a major cause of hospital admissions and death among HIV-infected patients 58.
Interestingly, HAART may positively affect the natural course of HCV infection. In a retrospective analysis of data from a therapeutic trial, Benhamou et al. demonstrated that patients who had received a protease inhibitor showed a lower rate of fibrosis progression than those who did not 30. In addition, a recent long-term cohort analysis showed that HCV--HIV coinfected patients on HAART had significantly lower liver-related mortality than patients receiving either insufficient or no anti-viral therapy 59. These benefits seem to outweigh the increased risk of hepatotoxicity of HAART, especially of the protease inhibitor ritonavir and the non-nucleoside reverse transcriptase inhibitor nevirapine 60. Thus, HAART should be offered to HCV--HIV coinfected patients.
Analyses of the effect of HCV infection on HIV disease progression yielded conflicting results [60,61] and is, therefore, still unclear. Recent data, however, suggest no negative effect of HCV coinfection on HIV infection if the analyses are corrected for the use of anti-retroviral therapy [58,62].
Very little information with respect to the specific mechanisms by which HIV accelerates the course of HCV infection is currently available. Direct viral interactions cannot be excluded although both viruses have different intracellular replication sites. However, it has been reported that HIV infection seems to facilitate HCV infection of extrahepatic cells 63. Although HCV RNA levels are typically higher in patients with HCV--HIV coinfection compared to patients with HCV only, there is no clear relationship between HCV viral load and the extent or progression of liver disease [51,64]. Since most epidemiological data suggest that accelerated progression of liver disease in HCV--HIV coinfected patients is linked to the loss of CD4+ T cells, the effect of HIV infection on the immune response to HCV is probably important in determining the natural course of HCV infection. Different mechanisms might contribute to the failure of immune control in this patient group, such as a selective loss of HCV-specific CD4+ T cell responses 65, loss of HCV-specific CD8+ T cell responses with declining CD4+ T cell counts 66, decreased interleukin-10 secretion of HCV specific intrahepatic CD4+ T cells 67, selective impairments in dendritic cell-associated functions 68 or modification of cytokine responses to HCV antigens 69. A possible contribution of HIV induced T cell dysfunction to the outcome of HCV infection is suggested by the recent observation that HCV can persist in HCV--HIV coinfected injection drug users who were re-exposed to HCV after having recovered from a prior infection 70.
3.2. Diagnosis and management
All HIV infected individuals should be screened for HCV infection. The approach to the diagnosis of HCV infection is similar to those without HIV infection [2,5]. However, loss of HCV antibodies (anti-HCV) can occur in a subset of HCV--HIV coinfected patients and may be associated with low CD4 counts. Therefore, in anti-HCV negative HIV-infected persons with unexplained liver disease serum HCV RNA should be determined 58. In >80% of anti-HCV positive HIV-infected patients serum HCV RNA is positive. In persons with undetectable HCV RNA on one occasion, the assay should be repeated at least once to rule out intermittent viremia 71. A liver biopsy should be considered before therapy to assess the grade and stage of the chronic hepatitis C. This information may be helpful for the decision to treat or not to treat the HCV infection, to estimate prognosis and to rule out other coexisting causes underlying the liver disease, such as drug-induced liver injury, iron overload and others.
All HCV--HIV coinfected persons should be advised to prevent additional liver damage, e.g. by abstaining from alcohol and by vaccination against HBV in case of negativity for HBsAg and anti-HBs and Hepatitis A Virus (HAV) in case of negativity for anti-HAV. The latter recommendation is based on the observed risk for fulminant hepatitis in persons with chronic HCV infection and the fact that HIV infected persons are at an increased risk for HAV infection 72.
3.3. Treatment
The current standard treatment of chronic hepatitis C is the combination of PEG-IFNα and ribavirin, a synthetic guanosine analogue [2,73]. Treatment is recommended for persons with chronic hepatitis C who are at greatest risk for progression to cirrhosis, characterized by serum HCV RNA positivity and histological findings of active inflammation (grade) and advanced fibrosis (stage). Since HIV infection is associated with a more rapid progression of chronic hepatits C to cirrhosis, the 2002 National Institutes of Health Consensus Development Conference Panel on the management of hepatitis C recommended that HCV--HIV coinfected patients should be considered for HCV treatment. The HCV treatment goals are elimination of HCV infection, risk reduction for liver failure and as well as better tolerance of anti-HIV therapy, such as HAART. Thus, patients with adequately controlled HIV disease, compensated liver disease and evidence of chronic hepatitis on liver biopsy should be evaluated for therapy.
Clinically significant comorbidities, e.g. drug addiction and psychiatric disorders, reduce eligibility for HCV treatment in a significant proportion (up to 70%) of HCV--HIV coinfected individuals [58,62].
Earlier non-randomized and uncontrolled studies with small group of patients have shown that IFNα monotherapy can lead to sustained viral clearance in a subset of HCV--HIV coinfected patients, ranging from 13 to 30% [62,74,75]. The response was associated with higher pre-treatment CD4+ T cell counts, lower HCV RNA levels and genotype 3a [62,74,75]. After randomized, placebo-controlled clinical trials clearly demonstrated that the combination therapy with IFNα plus ribavarin is as safe and more effective than IFNα monotherapy in HCV infected patients without HIV infection [5,73], the combination therapy was evaluated in HCV--HIV coinfected patients. While it is reasonably well tolerated in HCV--HIV coinfected patients 76, ribavirin should not be given to patients treated with the nucleoside reverse transcriptase inhibitor didanosine, because of the 5-fold increased risk of side effects related to mitochondrial toxicity, such as pancreatitis, lactate acidosis with liver failure and/or hepatic steatosis 76.
In a recent randomized placebo-controlled multicenter trial in patients with HCV--HIV coinfection 48 weeks of IFNα 3 million units three times per week plus either ribavirin 800mg/day or 16 weeks of placebo followed by ribavirin were compared. The overall response rate was low and significantly different in both groups (11.3 versus 5.6%). As expected, the response rate was lower in patients infected with HCV genotype 1 (2.5%) as compared to genotypes 2--4 (41.7%) 77. Thus, as in HCV infection only, genotypes appear to be the most significant prognostic factor for a sustained virological response to HCV also in HCV--HIV coinfected patients. The poor response rate also correlated with frequent treatment discontinuations. Interestingly, control of HIV infection seemed to improve rather than to worsen during anti-HCV therapy.
PEG-IFNα preparations were recently evaluated in HCV--HIV coinfected patients [58,62]. Two randomized controlled trials demonstrated that the combination of PEG-IFNα and ribavirin resulted in a much better sustained virological response than IFNα and ribavirin (27 versus 12% and 40 versus 12%, respectively) [78,79]. The highest response rates in both groups were observed among patients infected with an HCV genotype other than 1 (73 and 62%, respectively). These results were confirmed by two recent reports [80,81]. Importantly, monotherapy with PEG-IFNα was also significantly more effective than standard IFNα plus ribavirin (20 and 12%, respectively) 78. These results suggest that monotherapy with PEG-IFNα is a suitable alternative for patients who cannot tolerate ribavirin or have ribavirin contraindications.
These results, together with the poor prognosis for HCV--HIV coinfected patients justify broad use of anti-viral therapy in these patients. It is clear from these studies, however, that HCV infection is eradicated in a substantially lower proportion in HCV--HIV coinfected patients than in patients infected with HCV only. The reasons for the lower response rates in HCV--HIV coinfected patients may be a higher pre-treatment HCV RNA level, a higher prevalence of genotype 1, lower compliance with therapy, stronger side effects of PEG-IFNα and ribavirin, higher prevalence of advanced liver disease and drug--drug interactions that lead to more frequent discontinuation of treatment or dose reductions. Indeed, side effects of IFNα and ribavirin may occur more frequently, and be more severe in HCV--HIV coinfected patients because HCV treatment may induce or exacerbate HIV-related complications such as anaemia, neutropenia or depression. However, while in earlier studies withdrawal due to adverse events was as frequent as 29%, in recent studies using PEG-IFNα and ribavirin, the types and frequencies of adverse advents were similar to those previously reported in patients with HCV infection only [78,79,82]. Importantly, anti-viral therapy had a positive effect on liver disease progression also in patients without a sustained virological response. Among subjects without a virological response who underwent liver biopsy, >30% had histologic evidence of improvement, despite the absence of a significant decrease in HCV levels 79. Thus, maintenance therapy with IFNα should be considered for HCV--HIV coinfected patients with moderate to advanced fibrosis. IFNα monotherapy has no effect on HIV replication and results in a decline of CD4+ T cell counts that is reversible after termination of therapy. The recommendations for the management and therapy of HCV--HIV coinfected patients are summarized in Table 2.
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In general, liver transplantation is the treatment of choice for end-stage liver disease independent of the underlying cause(s). For patients with HIV infection, however, it is still considered experimental. Currently, several liver transplantation centers are investigating the feasibility of liver transplantation in HCV--HIV coinfected patients 83.
4. Summary and perspectives
Because of common routes of transmission, HIV-infected patients are frequently coinfected with HBV or HCV. HIV coinfection accelerates the natural course of hepatitis B and of hepatitis C. Therefore, effective treatment strategies for these special difficult-to-treat patient groups are urgently needed. The discovery of effective and well tolerated nucleos(t)ide analogues against HBV has greatly improved the perspectives for HBV--HIV coinfected patients. New nucleos(t)ide analogues, such as entecavir, clevudine, emtricitabine, and telbivudine, are currently being evaluated in clinical trials. However, drug resistance is likely to develop against all these compounds and future efforts should be aimed at developing effective and well tolerated combination therapy regimens. These and entirely novel anti-viral strategies that are currently being explored in the laboratory should result in more effective therapeutic strategies also for HBV--HIV coinfected patients groups.
In patients with chronic HCV infection, the combination of PEG-IFN and ribavirin greatly improved the virological response rates and the histological outcome of HCV infection HCV--HIV coinfected patients. However, only a small fraction of patients, especially those infected with genotype 1a, responds to combination therapy. Therefore, the novel therapeutic concepts need to be developed and evaluated that should result in a more efficacious treatment modalities, especially in HCV--HIV coinfected patients.
Above all, the implementation of measures to reduce HBV, HCV as well as HIV infection are of paramount importance and should result in a significant reduction of HBV- and HCV-related liver disease and its associated morbidity and mortality, also in HIV infected patients. In this context the development of a vaccine against HCV and HIV infection, respectively, is of very high priority.
References
1. [1]Blum HE, Pe M. EASL consensus conference on hepatitis B. J Hepatol. 2003;39:.
2. [2]Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345:41--52. MEDLINE | CrossRef
3. [3]Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000—summary of a workshop. Gastroenterology. 2001;120:1828--1853. MEDLINE
4. [4]Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology. 2004;39:857--861. MEDLINE | CrossRef
5. [5]Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet. 2003;362:2095--2100.
6. [6]Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147--1171. MEDLINE | CrossRef
7. [7]National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C 2002 (June 10--12 2002). Gastroenterology 2002; 123: 2082--99.
8. [8]Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med. 2004;350:1118--1129. CrossRef
9. [9]Mahoney FJ. Update on diagnosis, management, and prevention of hepatitis B virus infection. Clin Microbiol Rev. 1999;12:351--366. MEDLINE
10. [10]Homann C, Krogsgaard K, Pedersen C, Andersson P, Nielsen JO. High incidence of hepatitis B infection and evolution of chronic hepatitis B infection in patients with advanced HIV infection. J Acquir Immune Defic Syndr. 1991;4:416--420. MEDLINE
11. [11]Rustgi VK, Hoofnagle JH, Gerin JL, Gelmann EP, Reichert CM, Cooper JN, et al.. Hepatitis B virus infection in the acquired immunodeficiency syndrome. Ann Intern Med. 1984;101:795--797. MEDLINE
12. [12]Bodsworth NJ, Cooper DA, Donovan B. The influence of human immunodeficiency virus type 1 infection on the development of the hepatitis B virus carrier state. J Infect Dis. 1991;163:1138--1140. MEDLINE
13. [13]Gilson RJ, Hawkins AE, Beecham MR, Ross E, Waite J, Briggs M, et al.. Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection. AIDS. 1997;11:597--606. MEDLINE | CrossRef
14. [14]Colin JF, Cazals-Hatem D, Loriot MA, Martinot-Peignoux M, Pham BN, Auperin A, et al.. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology. 1999;29:1306--1310. MEDLINE | CrossRef
15. [15]Thio CL. Hepatitis B in the human immunodeficiency virus-infected patient: epidemiology, natural history, and treatment. Semin Liver Dis. 2003;23:125--136. MEDLINE | CrossRef
16. [16]Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, et al.. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology. 1999;30:1054--1058. MEDLINE | CrossRef
17. [17]Thio CL, Seaberg EC, Skolasky R, Phair J, Visscher B, Munoz A, et al.. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360:1921--1926. MEDLINE
18. [18]Rey D, Krantz V, Partisani M, et al.. Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients. Effects on HIV-1 viral load. Vaccine. 2000;18:1161--1165. MEDLINE | CrossRef
19. [19]Keet IP, van Doornum G, Safary A, Coutinho RA. Insufficient response to hepatitis B vaccination in HIV-positive homosexual men. AIDS. 1992;6:509--510. MEDLINE
20. [20]Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34:1225--1241. MEDLINE | CrossRef
21. [21]Brook MG, Karayiannis P, Thomas HC. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology. 1989;10:761--763. MEDLINE
22. [22]Perrillo RP, Mason AL. Therapy for hepatitis B virus infection. Gastroenterol Clin North Am. 1994;23:581--601. MEDLINE
23. [23]Wong DK, Yim C, Naylor CD, et al.. Interferon alfa treatment of chronic hepatitis B: randomized trial in a predominantly homosexual male population. Gastroenterology. 1995;108:165--171. MEDLINE
24. [24]Visco G, Alba L, Grisetti S, et al.. Zidovudine plus interferon alfa-2b treatment in patients with HIV and chronic active viral hepatitis. Gut. 1993;34:S107--S108.
25. [25]Di Martino V, Rufat P, Boyer N, et al.. The influence of human immunodeficiency virus coinfection on chronic hepatitis C in injection drug users: a long-term retrospective cohort study. Hepatology. 2001;34:1193--1199. MEDLINE | CrossRef
26. [26]Di Martino V, Thevenot T, Colin JF, et al.. Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B. Gastroenterology. 2002;123:1812--1822. MEDLINE | CrossRef
27. [27]Benhamou Y, Katlama C, Lunel F, et al.. Effects of lamivudine on replication of hepatitis B virus in HIV-infected men. Ann Intern Med. 1996;125:705--712. MEDLINE
28. [28]Dore GJ, Cooper DA, Barrett C, et al.. Dual efficacy of lamivudine treatment in human immunodeficiency virus/hepatitis B virus-coinfected persons in a randomized, controlled study (CAESAR). The CAESAR Coordinating Committee. J Infect Dis. 1999;180:607--613. MEDLINE | CrossRef
29. [29]Lim SG, Wai CT, Rajnakova A, Kajiji T, Guan R. Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B. Gut. 2002;51:597--599. MEDLINE | CrossRef
30. [30]Benhamou Y, Di Martino V, Bochet M, et al.. Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy. Hepatology. 2001;34:283--287. MEDLINE | CrossRef
31. [31]Werle B, Cinquin K, Marcellin P, et al.. Evolution of hepatitis B viral load and viral genome sequence during adefovir dipivoxil therapy. J Viral Hepatol. 2004;11:74--83.
32. [32]Thio CL. Management of chronic hepatitis B in the HIV-infected patient. AIDS Read. 2004;14:122--129See also pages 133, 136--7.
33. [33]Ristig MB, Crippin J, Aberg JA, et al.. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. J Infect Dis. 2002;186:1844--1847Epub 2002 Nov 1822. MEDLINE | CrossRef
34. [34]Nelson M, Portsmouth S, Stebbing J, et al.. An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected individuals. AIDS. 2003;17:F7--F10. CrossRef
35. [35]van Bommel F, Wunsche T, Mauss S, et al.. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology. 2004;40:1421--1425. MEDLINE | CrossRef
36. [36]Benhamou Y, Poynard T. Treatment of chronic hepatitis B virus infection in patients co-infected with human immunodeficiency virus. J Hepatol. 2003;39:S194--S199.
37. [37]Roland ME, Stock PG. Review of solid-organ transplantation in HIV-infected patients. Transplantation. 2003;75:425--429. MEDLINE
38. [38]Alter MJ, Margolis HS, Krawczynski K, et al.. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med. 1992;327:1899--1905. MEDLINE
39. [39]Alter MJ, Kruszon-Moran D, Nainan OV, et al.. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556--562. MEDLINE | CrossRef
40. [40]Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34:831--837Epub 2002 Feb 2006. CrossRef
41. [41]Saillour F, Dabis F, Dupon M, et al.. Prevalence and determinants of antibodies to hepatitis C virus and markers for hepatitis B virus infection in patients with HIV infection in Aquitaine. Groupe d'Epidemiologie Clinique du SIDA en Aquitaine. Br Med J. 1996;313:461--464.
42. [42]Gibb DM, Goodall RL, Dunn DT, et al.. Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission. Lancet. 2000;356:904--907. MEDLINE
43. [43]Palella FJ, Delaney KM, Moorman AC, et al.. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338:853--860. MEDLINE | CrossRef
44. [44]Sulkowski MS, Mast EE, Seeff LB, Thomas DL. Hepatitis C virus infection as an opportunistic disease in persons infected with human immunodeficiency virus. Clin Infect Dis. 2000;30:S77--S84. CrossRef
45. [45]Thomas DL, Astemborski J, Rai RM, et al.. The natural history of hepatitis C virus infection: host, viral, and environmental factors. J Am Med Assoc. 2000;284:450--456. MEDLINE
46. [46]Piasecki BA, Lewis JD, Reddy KR, et al.. Influence of alcohol use, race, and viral coinfections on spontaneous HCV clearance in a US veteran population. Hepatology. 2004;40:892--899. MEDLINE | CrossRef
47. [47]Monga HK, Rodriguez-Barradas MC, Breaux K, et al.. Hepatitis C virus infection-related morbidity and mortality among patients with human immunodeficiency virus infection. Clin Infect Dis. 2001;33:240--247Epub 2001 Jun 2015. MEDLINE | CrossRef
48. [48]Graham CS, Baden LR, Yu E, et al.. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33:562--569Epub 2001 Jul 2006. MEDLINE | CrossRef
49. [49]Darby SC, Ewart DW, Giangrande PL, et al.. Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. UK Haemophilia Centre Directors' Organisation. Lancet. 1997;350:1425--1431. MEDLINE
50. [50]Eyster ME, Fried MW, Di Bisceglie AM, Goedert JJ. Increasing hepatitis C virus RNA levels in hemophiliacs: relationship to human immunodeficiency virus infection and liver disease. Multicenter Hemophilia Cohort Study. Blood. 1994;84:1020--1023. MEDLINE
51. [51]Eyster ME, Diamondstone LS, Lien JM, et al.. Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. The Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr. 1993;6:602--610. MEDLINE
52. [52]Lesens O, Deschenes M, Steben M, Belanger G, Tsoukas CM. Hepatitis C virus is related to progressive liver disease in human immunodeficiency virus-positive hemophiliacs and should be treated as an opportunistic infection. J Infect Dis. 1999;179:1254--1258. MEDLINE | CrossRef
53. [53]Ragni MV, Belle SH. Impact of human immunodeficiency virus infection on progression to end-stage liver disease in individuals with hemophilia and hepatitis C virus infection. J Infect Dis. 2001;183:1112--1115Epub 2001 Mar 1101. MEDLINE | CrossRef
54. [54]Soto B, Sanchez-Quijano A, Rodrigo L, et al.. Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis. J Hepatol. 1997;26:1--5. Abstract | Abstract + References | PDF (577 KB) | MEDLINE | CrossRef
55. [55]Garcia-Samaniego J, Rodriguez M, Berenguer J, et al.. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C. Am J Gastroenterol. 2001;96:179--183. MEDLINE | CrossRef
56. [56]Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35--S50.
57. [57]Puoti M, Bonacini M, Spinetti A, et al.. Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus. J Infect Dis. 2001;183:134--137Epub 2000 Nov 2016. MEDLINE | CrossRef
58. [58]Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected person. Ann Intern Med. 2003;138:197--207.
59. [59]Qurishi N, Kreuzberg C, Luchters G, et al.. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet. 2003;362:1708--1713.
60. [60]Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. J Am Med Assoc. 2002;288:199--206. MEDLINE
61. [61]Greub G, Ledergerber B, Battegay M, et al.. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet. 2000;356:1800--1805. MEDLINE
62. [62]Rockstroh JK, Spengler U. HIV and hepatitis C virus co-infection. Lancet Infect Dis. 2004;4:437--444.
63. [63]Laskus T, Radkowski M, Piasek A, et al.. Hepatitis C virus in lymphoid cells of patients coinfected with human immunodeficiency virus type 1: evidence of active replication in monocytes/macrophages and lymphocytes. J Infect Dis. 2000;181:442--448. MEDLINE | CrossRef
64. [64]Sherman KE, O'Brien J, Gutierrez AG, et al.. Quantitative evaluation of hepatitis C virus RNA in patients with concurrent human immunodeficiency virus infections. J Clin Microbiol. 1993;31:2679--2682. MEDLINE
65. [65]Lauer GM, Nguyen TN, Day CL, et al.. Human immunodeficiency virus type 1-hepatitis C virus coinfection: intraindividual comparison of cellular immune responses against two persistent viruses. J Virol. 2002;76:2817--2826. MEDLINE | CrossRef
66. [66]Kim AY, Lauer GM, Ouchi K, et al.. The magnitude and breadth of hepatitis C virus-specific CD8+ T cells depend on absolute CD4+ T cell count in HIV-1 coinfected individuals. Blood. 2004;30:30.
67. [67]Graham CS, Curry M, He Q, et al.. Comparison of HCV-specific intrahepatic CD4+ T cells in HIV/HCV versus HCV. Hepatology. 2004;40:125--132. MEDLINE | CrossRef
68. [68]Anthony DD, Yonkers NL, Post AB, et al.. Selective impairments in dendritic cell-associated function distinguish hepatitis C virus and HIV infection. J Immunol. 2004;172:4907--4916. MEDLINE
69. [69]Woitas RP, Rockstroh JK, Beier I, et al.. Antigen-specific cytokine response to hepatitis C virus core epitopes in HIV/hepatitis C virus-coinfected patients. AIDS. 1999;13:1313--1322. MEDLINE
70. [70]Mehta SH, Cox A, Hoover DR, et al.. Protection against persistence of hepatitis C. Lancet. 2002;359:1478--1483. MEDLINE
71. [71]Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology. 1999;29:908--914. MEDLINE | CrossRef
72. [72]Vento S, Garofano T, Renzini C, et al.. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med. 1998;338:286--290. MEDLINE | CrossRef
73. [73]Poynard T, Marcellin P, Lee SS, et al.. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet. 1998;352:1426--1432. MEDLINE
74. [74]Mauss S, Klinker H, Ulmer A, et al.. Response to treatment of chronic hepatitis C with interferon alpha in patients infected with HIV-1 is associated with higher CD4+ cell count. Infection. 1998;26:16--19. MEDLINE
75. [75]Soriano V, Garcia-Samaniego J, Bravo R, et al.. Interferon alpha for the treatment of chronic hepatitis C in patients infected with human immunodeficiency virus. Hepatitis-HIV Spanish Study Group. Clin Infect Dis. 1996;23:585--591. MEDLINE
76. [76]Sterling RK, Sulkowski MS. Hepatitis C virus in the setting of HIV or hepatitis B virus coinfection. Semin Liver Dis. 2004;24:61--68. CrossRef
77. [77]Brau N, Rodriguez-Torres M, Prokupek D, et al.. Treatment of chronic hepatitis C in HIV/HCV-coinfection with interferon alpha-2b+ full-course vs. 16-week delayed ribavirin. Hepatology. 2004;39:989--998. MEDLINE | CrossRef
78. [78]Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al.. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351:438--450. CrossRef
79. [79]Chung RT, Andersen J, Volberding P, et al.. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004;351:451--459. CrossRef
80. [80]Carrat F, Bani-Sadr F, Pol S, et al.. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. J Am Med Assoc. 2004;292:2839--2848. CrossRef
81. [81]Laguno M, Murillas J, Blanco JL, et al.. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS. 2004;18:F27--F36.
82. [82]Pawlotsky JM. Treating hepatitis C in difficult-to-treat patients. N Engl J Med. 2004;351:422--423. CrossRef
83. [83]Norris S, Taylor C, Muiesan P, et al.. Outcomes of liver transplantation in HIV-infected individuals: the impact of HCV and HBV infection. Liver Transpl. 2004;10:1271--1278.
Hepatitis B or hepatitis C and HIV-infection
Journal of Hepatology January 2005
Robert Thimme, Hans Christian Spangenberg, Hubert E. Blum*Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, D-79016 Freiburg, Germany
Article Outline1. Introduction2. HBV--HIV coinfection2.1. Natural history2.2. Diagnosis and management2.3. Treatment3. HCV--HIV coinfection3.1. Natural course3.2. Diagnosis and management3.3. Treatment4. Summary and perspectivesReferences
"...there is consensus that HIV infection accelerates HCV related liver disease, especially when immunodeficiency progresses. Thus, with increasing survival of HIV-infected patients due to HAART and prophylaxis of opportunistic infections, HCV related morbidity and mortality increases and has already become a major cause of hospital admissions and death among HIV-infected patients...
... All patients with HIV infection should be screened for HBV infection... Up to 80% of HIV-infected patients have been exposed to HBV and up to 10% have chronic hepatitis B... The optimal screening strategy has not yet been defined but is usually based on the determination of HBsAg (hepatitis B surface antigen) and anti-HBs... Despite the initially mild clinical course, the HBV-related liver disease in HIV-infected patients is more progressive,... The Multicenter Cohort Study, for example, has reported a liver-related mortality rate of 14.2 per 1000 person years in HBV--HIV coinfected men compared to 0.8 per 1000 person years in men infected with HBV only...All HIV infected individuals should be screened for HCV infection... loss of HCV antibodies (anti-HCV) can occur in a subset of HCV--HIV coinfected patients and may be associated with low CD4 counts. Therefore, in anti-HCV negative HIV-infected persons with unexplained liver disease serum HCV RNA should be determined... A liver biopsy should be considered before therapy to assess the grade and stage of the chronic hepatitis C. This information may be helpful for the decision to treat or not to treat the HCV infection, to estimate prognosis and to rule out other coexisting causes underlying the liver disease, such as drug-induced liver injury, iron overload and others...
...liver disease and in particular hepatitis C has emerged as one of the most important causes of morbidity and mortality in HIV-infected patients... HIV coinfection has been associated with higher HCV RNA levels, a more rapid progression of the chronic liver disease and a higher incidence of cirrhosis and HCC (liver cancer)... persons with HCV--HIV coinfection are three times more likely to develop cirrhosis or advanced liver disease than patients infected with HCV only...prognostic factors include gender, duration of HCV infection and alcohol consumption...HIV infection may also accelerate the development of HCC in patients with chronic hepatitis C since HCC occurs...
... HAART may positively affect the natural course of HCV infection... These benefits seem to outweigh the increased risk of hepatotoxicity of HAART... HAART should be offered to HCV--HIV coinfected patients...
... Very little information with respect to the specific mechanisms by which HIV accelerates the course of HCV infection is currently available... data suggest that accelerated progression of liver disease in HCV--HIV coinfected patients is linked to the loss of CD4+ T cells...
... Treatment is recommended for persons with chronic hepatitis C who are at greatest risk for progression to cirrhosis, characterized by serum HCV RNA positivity and histological findings of active inflammation (grade) and advanced fibrosis (stage)...
... HCV treatment goals are elimination of HCV infection, risk reduction for liver failure and as well as better tolerance of anti-HIV therapy, such as HAART. Thus, patients with adequately controlled HIV disease, compensated liver disease and evidence of chronic hepatitis on liver biopsy should be evaluated for therapy...
...treatment study results in coinfected patients together with the poor prognosis for HCV--HIV coinfected patients justify broad use of anti-viral therapy in these patients..."
1. IntroductionChronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is common among patients infected with the human immunodeficiency virus (HIV), due to the common epidemilogical risks. Recommendations for the management of patients with chronic hepatitis B and C, although continuously evolving, have recently been formulated in the US and Europe [1--7]. However, for special patient groups treatment modalities are less well defined and therapeutic options often have to be evaluated on an individual basis. These include among others patients with advanced liver disease or decompensated liver cirrhosis, transplant recipients, patients with asymptomatic hepatitis B or hepatitis C with normal ALT levels undergoing immunosuppressive therapy, and patients coinfected with HBV or HBV and hepatitis delta virus (HDV) and HIV or HCV and HIV, HBV, HCV and HIV or HBV, HDV, HCV and HIV. In the following, we will briefly review the natural course, management and current treatment modalities for patients coinfected with HBV or HCV and HIV.
2. HBV--HIV coinfectionHBV is a non-cytopathic, hepatotropic virus with more than 350 million infected individuals worldwide 8. It is the leading cause of chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC) and is associated with significant morbidity and mortality 9. HIV and HBV have common routes of transmission. Up to 80% of HIV-infected patients have been exposed to HBV and up to 10% have chronic hepatitis B [10,11]. Despite an effective vaccine against HBV, which is recommended for individuals at high risk of exposure, there is a rising incidence of acute HBV infection in HIV-infected individuals.
2.1. Natural historyIn otherwise healthy adults, acute HBV infection is eliminated in 90--95%, associated with a broad and multispecific cellular immune response and the loss of hepatitis B surface antigen (HBsAg) and seroconversion to anti-HBs antibodies that convey protection against reinfection 9. In HIV-infected patients, however, the clearance rates of HBsAg and hepatitis B e antigen (HBeAg) are reduced compared to individuals without HIV infection, possibly related to the degree of immunosuppression [12,13]. This phenomenon can be explained by the impaired cellular immune responses in HIV infection that lead to a higher chronicity rate of HBV. However, due to the weak immune responses against HBV, the clinical course of HBV infection (ALT elevations) is usually benign and frequently asymptomatic, although HBV replication is enhanced. Despite the initially mild clinical course, the HBV-related liver disease in HIV-infected patients is more progressive, including the development of cirrhosis and its complications, compared to patients with HBV infection only and thus contributes significantly to the morbidity and mortality of HIV-infected patients [13--16]. The increase in liver-related mortality appears to be particularly pronounced since the introduction of highly active anti-retroviral therapy (HAART). The Multicenter Cohort Study, for example, has reported a liver-related mortality rate of 14.2 per 1000 person years in HBV--HIV coinfected men compared to 0.8 per 1000 person years in men infected with HBV only 17. Interestingly, in this study the individuals with lower CD4 T cells were at greater risk. The pathophysiologic basis for this observation is unclear at present, but may involve increased liver injury as a consequence of immune restoration under HAART, hepatotoxicity of certain anti-HIV drugs and the longer life expectancy of patients treated with HAART.
2.2. Diagnosis and managementAll patients with HIV infection should be screened for HBV infection. The optimal screening strategy has not yet been defined but is usually based on the determination of HBsAg and anti-HBs. In the case that both markers are negative, an active hepatitis B vaccine should be administered. Vaccination is safe in HIV infected patients, but a higher proportion of these patients may not develop protective immunity (30% primary non-response to HBV vaccine in HIV infected individuals versus 2.5% in healthy individuals) or are more likely to lose their immunity over time [18,19]. Testing for HBsAg and anti-HBs, however, will not identify patients with occult HBV infection who are typically serologically positive for anti-HBc only. In this situation anti-HBc and serum HBV DNA should be determined. Table 1 gives an overview of the different serological patterns after HBV infection.
2.3. TreatmentThe aim of HBV treatment is to reduce liver inflammation, to prevent progression of disease towards liver cirrhosis and HCC and ideally to eradicate HBV infection. The AASLD recommends treatment of HBV in patients without HIV infection in HBeAg positive chronic hepatitis with evidence of liver injury (ALT>2×upper limit of or necroinflammation on biopsy) and in HBeAg negative chronic hepatitis B with HBV DNA levels >105copies/ml 20. The same criteria can be applied to patients coinfected with HIV, taking into account the stage of the HIV disease. A liver biopsy may be helpful for the decision to treat or not to treat the HBV infection. A delayed initiation of therapy may reduce HAART toxicity or prevent viral resistance in HBV--HIV coinfected individuals. Currently there are three commercially available treatment modalities for chronic HBV infection: interferon alfa (IFNα), lamivudine and adefovir.
IFNα is usually given as subcutaneous injection of 5 million units daily or 10 million units three times per week 20. It is a cytokine with anti-viral and immunomodulatory effects. Its highest effectiveness has been demonstrated in patients with HBeAg, high ALT levels (>2×upper limit of normal) and lower HBV DNA levels (<2.8×107copies/ml) [21,22]. Based on these selection criteria, IFNα treatment for 16 weeks results in sustained response rate of approx. 33% 23. With respect to HBV therapy in HBV--HIV coinfected patients, the limited information currently available indicates that the response rate decreased in coinfection as compared to HBV infection only. In the above mentioned meta-analysis of randomized trials with a total of 837 HBV infected persons 55 individuals were coinfected with HIV and showed a significantly lower seroconversion rate 23. However, most of the studies were not randomized according to the HIV status and did not take the CD4 T cell count or the ALT levels into account. Trials performed in the pre-HAART era also showed reduced sustained response rates in coinfected patients [23--26]. In summary, IFNα treatment in HBV--HIV coinfection may be an option in selected patients as described above with good immune function (CD4 cell count >500). Furthermore, therapy with pegylated (PEG) IFNα may be more efficacious in treating HBV in HIV positive individuals. However, randomized controlled studies are needed to answer this important question.
The nucleos(t)ide analogues lamivudine (LAM) and adefovir (ADV) are commercially available for the treatment of chronic HBV infection. LAM, which has excellent anti-viral activity against HIV and HBV suppresses viral replication of both viruses and results in improvement of the histological activity index (HAI). In HIV infection LAM is administered at a dose of 150mg twice as a component of HAART regimen while in patients with HBV infection only the dose 100mg once a day. In studies of HBV--HIV coinfected patients, HBeAg seroconversion rates of 22--28% can be achieved, similar to patients with HBV infection only [27,28]. However, long-term treatment with LAM is limited by the development of LAM-resistant mutants that usually have mutations in the YMDD motif of the catalytic unit of the polymerase gene. Resistance seems to emerge in HBV--HIV infected patients more rapidly than in HIV-negative patients. Rates of LAM resistance as high as 50% at 2 and 90% at 4 years have been reported 16. Flares in liver disease usually indicate the development of LAM resistance. LAM therapy should not be stopped, however, in these cases because severe recurrent hepatitis with even fatal complications may evolve 29. In this situation a therapy with the nucleotide analogue ADV should be instituted that efficiently suppresses HBV replication and appears to even decrease the pool of covalently closed circular (ccc) HBV DNA [30,31]. It is unclear whether ADV should be added to LAM therapy or given sequentially. At a dose of 10mg/d ADV is well tolerated and does not affect HIV RNA levels or CD4+ T cell counts. Interestingly, there is a transient increase in serum ALT levels by week 8--24 occurs in a number of patients treated with ADV, possibly related to immune reconstitution under effective anti-viral therapy. To date, ADV resistant mutants appear to be rather uncommon (1.6% after 96 weeks of treatment) 32. Tenofovir disoproxil fumarate (TDF), another nucleotide analogue with activity against HIV at a dose of 300mg/d, has recently emerged as an attractive alternative for HIV-infected patients with LAM-resistant HBV infection [33,34]. Several pilot studies have shown excellent effectiveness against HBV. Based on recent data, TDF may become an alternative to ADV for the treatment of patients with LAM-resistant HBV infection 35. To date, however, TDF has been licensed for the treatment of HIV infection only.
Due to the limited data on the treatment of HBV--HIV coinfection, no evidence based guidelines exist. In principle, treatment decision have to be made on an individual basis and should consider the aspects guiding the treatment decisions mentioned above 36.
Liver transplantation in patients with advanced liver cirrhosis and/or HCC in HBV--HIV coinfection might be an option for selected patients. Recent reports indicate in a limited number of patients that the outcome of liver transplantation in selected patients with HIV infection may be as good as in those without HIV infection 37.
3. HCV--HIV coinfectionCoinfection with HIV and HCV is common in Europe and the USA, affecting approximately 25% of HIV-infected individuals and 5--10% of HCV-infected patients [38--40]. The high prevalence of HCV--HIV coinfections is attributed to common risk factors for transmission, i.e. blood and blood products. However, since HCV is about 10 times more infectious than HIV, coinfection is more common in patients with high volume exposure to blood. Thus, the prevalence of HCV coinfection in HIV-infected persons depends largely on the mode of HIV transmission. It is high in patients after parenteral transmission such as injecting drug use (91%) or transfusion of blood or blood products (71%), and comparatively low after sexually transmitted HIV infection (7.3%) 41. HCV is transmitted to 2--5% of infants born to HCV-infected mothers and the incidence increases if the mother is coinfected with HIV 42.
Since the introduction of HAART, the incidence of most opportunistic infections and overall mortality have sharply declined in HIV-infected patients 43. At the same time, liver disease and in particular hepatitis C has emerged as one of the most important causes of morbidity and mortality in these patients 44.
3.1. Natural courseHIV infection appears to adversely affect the outcome of acute and chronic HCV infection. Indeed, spontaneous recovery from HCV infection occurs in only 5--10% of HIV infected patients and even less in those with low CD4+ T cell counts. By comparison, HCV can be cleared in up to 35% in HIV-uninfected patients [2,38,45,46]. In persons with chronic HCV infection, HIV coinfection has been associated with higher HCV RNA levels, a more rapid progression of the chronic liver disease and a higher incidence of cirrhosis and HCC [16,25,47--56]. Indeed, persons with HCV--HIV coinfection are three times more likely to develop cirrhosis or advanced liver disease than patients infected with HCV only 48. In the UK National Haemophilia Register men with haemophilia exposed to HCV and HIV were 4.6-fold more likely to die from liver disease than HIV infected men without HCV infection 49. The level of CD4 immunosuppression has emerged as one of the most important determinants of progression to liver disease 57. Additional prognostic factors include gender, duration of HCV infection and alcohol consumption. HIV infection may also accelerate the development of HCC in patients with chronic hepatitis C since HCC occurs at a younger age in coinfected patients compared with those infected with HCV only 55. Taken together, there is consensus that HIV infection accelerates HCV related liver disease, especially when immunodeficiency progresses. Thus, with increasing survival of HIV-infected patients due to HAART and prophylaxis of opportunistic infections, HCV related morbidity and mortality increases and has already become a major cause of hospital admissions and death among HIV-infected patients 58.
Interestingly, HAART may positively affect the natural course of HCV infection. In a retrospective analysis of data from a therapeutic trial, Benhamou et al. demonstrated that patients who had received a protease inhibitor showed a lower rate of fibrosis progression than those who did not 30. In addition, a recent long-term cohort analysis showed that HCV--HIV coinfected patients on HAART had significantly lower liver-related mortality than patients receiving either insufficient or no anti-viral therapy 59. These benefits seem to outweigh the increased risk of hepatotoxicity of HAART, especially of the protease inhibitor ritonavir and the non-nucleoside reverse transcriptase inhibitor nevirapine 60. Thus, HAART should be offered to HCV--HIV coinfected patients.
Analyses of the effect of HCV infection on HIV disease progression yielded conflicting results [60,61] and is, therefore, still unclear. Recent data, however, suggest no negative effect of HCV coinfection on HIV infection if the analyses are corrected for the use of anti-retroviral therapy [58,62].
Very little information with respect to the specific mechanisms by which HIV accelerates the course of HCV infection is currently available. Direct viral interactions cannot be excluded although both viruses have different intracellular replication sites. However, it has been reported that HIV infection seems to facilitate HCV infection of extrahepatic cells 63. Although HCV RNA levels are typically higher in patients with HCV--HIV coinfection compared to patients with HCV only, there is no clear relationship between HCV viral load and the extent or progression of liver disease [51,64]. Since most epidemiological data suggest that accelerated progression of liver disease in HCV--HIV coinfected patients is linked to the loss of CD4+ T cells, the effect of HIV infection on the immune response to HCV is probably important in determining the natural course of HCV infection. Different mechanisms might contribute to the failure of immune control in this patient group, such as a selective loss of HCV-specific CD4+ T cell responses 65, loss of HCV-specific CD8+ T cell responses with declining CD4+ T cell counts 66, decreased interleukin-10 secretion of HCV specific intrahepatic CD4+ T cells 67, selective impairments in dendritic cell-associated functions 68 or modification of cytokine responses to HCV antigens 69. A possible contribution of HIV induced T cell dysfunction to the outcome of HCV infection is suggested by the recent observation that HCV can persist in HCV--HIV coinfected injection drug users who were re-exposed to HCV after having recovered from a prior infection 70.
3.2. Diagnosis and managementAll HIV infected individuals should be screened for HCV infection. The approach to the diagnosis of HCV infection is similar to those without HIV infection [2,5]. However, loss of HCV antibodies (anti-HCV) can occur in a subset of HCV--HIV coinfected patients and may be associated with low CD4 counts. Therefore, in anti-HCV negative HIV-infected persons with unexplained liver disease serum HCV RNA should be determined 58. In >80% of anti-HCV positive HIV-infected patients serum HCV RNA is positive. In persons with undetectable HCV RNA on one occasion, the assay should be repeated at least once to rule out intermittent viremia 71. A liver biopsy should be considered before therapy to assess the grade and stage of the chronic hepatitis C. This information may be helpful for the decision to treat or not to treat the HCV infection, to estimate prognosis and to rule out other coexisting causes underlying the liver disease, such as drug-induced liver injury, iron overload and others.
All HCV--HIV coinfected persons should be advised to prevent additional liver damage, e.g. by abstaining from alcohol and by vaccination against HBV in case of negativity for HBsAg and anti-HBs and Hepatitis A Virus (HAV) in case of negativity for anti-HAV. The latter recommendation is based on the observed risk for fulminant hepatitis in persons with chronic HCV infection and the fact that HIV infected persons are at an increased risk for HAV infection 72.
3.3. TreatmentThe current standard treatment of chronic hepatitis C is the combination of PEG-IFNα and ribavirin, a synthetic guanosine analogue [2,73]. Treatment is recommended for persons with chronic hepatitis C who are at greatest risk for progression to cirrhosis, characterized by serum HCV RNA positivity and histological findings of active inflammation (grade) and advanced fibrosis (stage). Since HIV infection is associated with a more rapid progression of chronic hepatits C to cirrhosis, the 2002 National Institutes of Health Consensus Development Conference Panel on the management of hepatitis C recommended that HCV--HIV coinfected patients should be considered for HCV treatment. The HCV treatment goals are elimination of HCV infection, risk reduction for liver failure and as well as better tolerance of anti-HIV therapy, such as HAART. Thus, patients with adequately controlled HIV disease, compensated liver disease and evidence of chronic hepatitis on liver biopsy should be evaluated for therapy.
Clinically significant comorbidities, e.g. drug addiction and psychiatric disorders, reduce eligibility for HCV treatment in a significant proportion (up to 70%) of HCV--HIV coinfected individuals [58,62].
Earlier non-randomized and uncontrolled studies with small group of patients have shown that IFNα monotherapy can lead to sustained viral clearance in a subset of HCV--HIV coinfected patients, ranging from 13 to 30% [62,74,75]. The response was associated with higher pre-treatment CD4+ T cell counts, lower HCV RNA levels and genotype 3a [62,74,75]. After randomized, placebo-controlled clinical trials clearly demonstrated that the combination therapy with IFNα plus ribavarin is as safe and more effective than IFNα monotherapy in HCV infected patients without HIV infection [5,73], the combination therapy was evaluated in HCV--HIV coinfected patients. While it is reasonably well tolerated in HCV--HIV coinfected patients 76, ribavirin should not be given to patients treated with the nucleoside reverse transcriptase inhibitor didanosine, because of the 5-fold increased risk of side effects related to mitochondrial toxicity, such as pancreatitis, lactate acidosis with liver failure and/or hepatic steatosis 76.
In a recent randomized placebo-controlled multicenter trial in patients with HCV--HIV coinfection 48 weeks of IFNα 3 million units three times per week plus either ribavirin 800mg/day or 16 weeks of placebo followed by ribavirin were compared. The overall response rate was low and significantly different in both groups (11.3 versus 5.6%). As expected, the response rate was lower in patients infected with HCV genotype 1 (2.5%) as compared to genotypes 2--4 (41.7%) 77. Thus, as in HCV infection only, genotypes appear to be the most significant prognostic factor for a sustained virological response to HCV also in HCV--HIV coinfected patients. The poor response rate also correlated with frequent treatment discontinuations. Interestingly, control of HIV infection seemed to improve rather than to worsen during anti-HCV therapy.
PEG-IFNα preparations were recently evaluated in HCV--HIV coinfected patients [58,62]. Two randomized controlled trials demonstrated that the combination of PEG-IFNα and ribavirin resulted in a much better sustained virological response than IFNα and ribavirin (27 versus 12% and 40 versus 12%, respectively) [78,79]. The highest response rates in both groups were observed among patients infected with an HCV genotype other than 1 (73 and 62%, respectively). These results were confirmed by two recent reports [80,81]. Importantly, monotherapy with PEG-IFNα was also significantly more effective than standard IFNα plus ribavirin (20 and 12%, respectively) 78. These results suggest that monotherapy with PEG-IFNα is a suitable alternative for patients who cannot tolerate ribavirin or have ribavirin contraindications.
These results, together with the poor prognosis for HCV--HIV coinfected patients justify broad use of anti-viral therapy in these patients. It is clear from these studies, however, that HCV infection is eradicated in a substantially lower proportion in HCV--HIV coinfected patients than in patients infected with HCV only. The reasons for the lower response rates in HCV--HIV coinfected patients may be a higher pre-treatment HCV RNA level, a higher prevalence of genotype 1, lower compliance with therapy, stronger side effects of PEG-IFNα and ribavirin, higher prevalence of advanced liver disease and drug--drug interactions that lead to more frequent discontinuation of treatment or dose reductions. Indeed, side effects of IFNα and ribavirin may occur more frequently, and be more severe in HCV--HIV coinfected patients because HCV treatment may induce or exacerbate HIV-related complications such as anaemia, neutropenia or depression. However, while in earlier studies withdrawal due to adverse events was as frequent as 29%, in recent studies using PEG-IFNα and ribavirin, the types and frequencies of adverse advents were similar to those previously reported in patients with HCV infection only [78,79,82]. Importantly, anti-viral therapy had a positive effect on liver disease progression also in patients without a sustained virological response. Among subjects without a virological response who underwent liver biopsy, >30% had histologic evidence of improvement, despite the absence of a significant decrease in HCV levels 79. Thus, maintenance therapy with IFNα should be considered for HCV--HIV coinfected patients with moderate to advanced fibrosis. IFNα monotherapy has no effect on HIV replication and results in a decline of CD4+ T cell counts that is reversible after termination of therapy. The recommendations for the management and therapy of HCV--HIV coinfected patients are summarized in Table 2.
In general, liver transplantation is the treatment of choice for end-stage liver disease independent of the underlying cause(s). For patients with HIV infection, however, it is still considered experimental. Currently, several liver transplantation centers are investigating the feasibility of liver transplantation in HCV--HIV coinfected patients 83.
4. Summary and perspectivesBecause of common routes of transmission, HIV-infected patients are frequently coinfected with HBV or HCV. HIV coinfection accelerates the natural course of hepatitis B and of hepatitis C. Therefore, effective treatment strategies for these special difficult-to-treat patient groups are urgently needed. The discovery of effective and well tolerated nucleos(t)ide analogues against HBV has greatly improved the perspectives for HBV--HIV coinfected patients. New nucleos(t)ide analogues, such as entecavir, clevudine, emtricitabine, and telbivudine, are currently being evaluated in clinical trials. However, drug resistance is likely to develop against all these compounds and future efforts should be aimed at developing effective and well tolerated combination therapy regimens. These and entirely novel anti-viral strategies that are currently being explored in the laboratory should result in more effective therapeutic strategies also for HBV--HIV coinfected patients groups.
In patients with chronic HCV infection, the combination of PEG-IFN and ribavirin greatly improved the virological response rates and the histological outcome of HCV infection HCV--HIV coinfected patients. However, only a small fraction of patients, especially those infected with genotype 1a, responds to combination therapy. Therefore, the novel therapeutic concepts need to be developed and evaluated that should result in a more efficacious treatment modalities, especially in HCV--HIV coinfected patients.
Above all, the implementation of measures to reduce HBV, HCV as well as HIV infection are of paramount importance and should result in a significant reduction of HBV- and HCV-related liver disease and its associated morbidity and mortality, also in HIV infected patients. In this context the development of a vaccine against HCV and HIV infection, respectively, is of very high priority.
References1. [1]Blum HE, Pe M. EASL consensus conference on hepatitis B. J Hepatol. 2003;39:.
2. [2]Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345:41--52. MEDLINE | CrossRef
3. [3]Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000—summary of a workshop. Gastroenterology. 2001;120:1828--1853. MEDLINE
4. [4]Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology. 2004;39:857--861. MEDLINE | CrossRef
5. [5]Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet. 2003;362:2095--2100.
6. [6]Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147--1171. MEDLINE | CrossRef
7. [7]National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C 2002 (June 10--12 2002). Gastroenterology 2002; 123: 2082--99.
8. [8]Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med. 2004;350:1118--1129. CrossRef
9. [9]Mahoney FJ. Update on diagnosis, management, and prevention of hepatitis B virus infection. Clin Microbiol Rev. 1999;12:351--366. MEDLINE
10. [10]Homann C, Krogsgaard K, Pedersen C, Andersson P, Nielsen JO. High incidence of hepatitis B infection and evolution of chronic hepatitis B infection in patients with advanced HIV infection. J Acquir Immune Defic Syndr. 1991;4:416--420. MEDLINE
11. [11]Rustgi VK, Hoofnagle JH, Gerin JL, Gelmann EP, Reichert CM, Cooper JN, et al.. Hepatitis B virus infection in the acquired immunodeficiency syndrome. Ann Intern Med. 1984;101:795--797. MEDLINE
12. [12]Bodsworth NJ, Cooper DA, Donovan B. The influence of human immunodeficiency virus type 1 infection on the development of the hepatitis B virus carrier state. J Infect Dis. 1991;163:1138--1140. MEDLINE
13. [13]Gilson RJ, Hawkins AE, Beecham MR, Ross E, Waite J, Briggs M, et al.. Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection. AIDS. 1997;11:597--606. MEDLINE | CrossRef
14. [14]Colin JF, Cazals-Hatem D, Loriot MA, Martinot-Peignoux M, Pham BN, Auperin A, et al.. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology. 1999;29:1306--1310. MEDLINE | CrossRef
15. [15]Thio CL. Hepatitis B in the human immunodeficiency virus-infected patient: epidemiology, natural history, and treatment. Semin Liver Dis. 2003;23:125--136. MEDLINE | CrossRef
16. [16]Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, et al.. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology. 1999;30:1054--1058. MEDLINE | CrossRef
17. [17]Thio CL, Seaberg EC, Skolasky R, Phair J, Visscher B, Munoz A, et al.. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360:1921--1926. MEDLINE
18. [18]Rey D, Krantz V, Partisani M, et al.. Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients. Effects on HIV-1 viral load. Vaccine. 2000;18:1161--1165. MEDLINE | CrossRef
19. [19]Keet IP, van Doornum G, Safary A, Coutinho RA. Insufficient response to hepatitis B vaccination in HIV-positive homosexual men. AIDS. 1992;6:509--510. MEDLINE
20. [20]Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34:1225--1241. MEDLINE | CrossRef
21. [21]Brook MG, Karayiannis P, Thomas HC. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology. 1989;10:761--763. MEDLINE
22. [22]Perrillo RP, Mason AL. Therapy for hepatitis B virus infection. Gastroenterol Clin North Am. 1994;23:581--601. MEDLINE
23. [23]Wong DK, Yim C, Naylor CD, et al.. Interferon alfa treatment of chronic hepatitis B: randomized trial in a predominantly homosexual male population. Gastroenterology. 1995;108:165--171. MEDLINE
24. [24]Visco G, Alba L, Grisetti S, et al.. Zidovudine plus interferon alfa-2b treatment in patients with HIV and chronic active viral hepatitis. Gut. 1993;34:S107--S108.
25. [25]Di Martino V, Rufat P, Boyer N, et al.. The influence of human immunodeficiency virus coinfection on chronic hepatitis C in injection drug users: a long-term retrospective cohort study. Hepatology. 2001;34:1193--1199. MEDLINE | CrossRef
26. [26]Di Martino V, Thevenot T, Colin JF, et al.. Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B. Gastroenterology. 2002;123:1812--1822. MEDLINE | CrossRef
27. [27]Benhamou Y, Katlama C, Lunel F, et al.. Effects of lamivudine on replication of hepatitis B virus in HIV-infected men. Ann Intern Med. 1996;125:705--712. MEDLINE
28. [28]Dore GJ, Cooper DA, Barrett C, et al.. Dual efficacy of lamivudine treatment in human immunodeficiency virus/hepatitis B virus-coinfected persons in a randomized, controlled study (CAESAR). The CAESAR Coordinating Committee. J Infect Dis. 1999;180:607--613. MEDLINE | CrossRef
29. [29]Lim SG, Wai CT, Rajnakova A, Kajiji T, Guan R. Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B. Gut. 2002;51:597--599. MEDLINE | CrossRef
30. [30]Benhamou Y, Di Martino V, Bochet M, et al.. Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy. Hepatology. 2001;34:283--287. MEDLINE | CrossRef
31. [31]Werle B, Cinquin K, Marcellin P, et al.. Evolution of hepatitis B viral load and viral genome sequence during adefovir dipivoxil therapy. J Viral Hepatol. 2004;11:74--83.
32. [32]Thio CL. Management of chronic hepatitis B in the HIV-infected patient. AIDS Read. 2004;14:122--129See also pages 133, 136--7.
33. [33]Ristig MB, Crippin J, Aberg JA, et al.. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. J Infect Dis. 2002;186:1844--1847Epub 2002 Nov 1822. MEDLINE | CrossRef
34. [34]Nelson M, Portsmouth S, Stebbing J, et al.. An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected individuals. AIDS. 2003;17:F7--F10. CrossRef
35. [35]van Bommel F, Wunsche T, Mauss S, et al.. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology. 2004;40:1421--1425. MEDLINE | CrossRef
36. [36]Benhamou Y, Poynard T. Treatment of chronic hepatitis B virus infection in patients co-infected with human immunodeficiency virus. J Hepatol. 2003;39:S194--S199.
37. [37]Roland ME, Stock PG. Review of solid-organ transplantation in HIV-infected patients. Transplantation. 2003;75:425--429. MEDLINE
38. [38]Alter MJ, Margolis HS, Krawczynski K, et al.. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med. 1992;327:1899--1905. MEDLINE
39. [39]Alter MJ, Kruszon-Moran D, Nainan OV, et al.. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556--562. MEDLINE | CrossRef
40. [40]Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34:831--837Epub 2002 Feb 2006. CrossRef
41. [41]Saillour F, Dabis F, Dupon M, et al.. Prevalence and determinants of antibodies to hepatitis C virus and markers for hepatitis B virus infection in patients with HIV infection in Aquitaine. Groupe d'Epidemiologie Clinique du SIDA en Aquitaine. Br Med J. 1996;313:461--464.
42. [42]Gibb DM, Goodall RL, Dunn DT, et al.. Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission. Lancet. 2000;356:904--907. MEDLINE
43. [43]Palella FJ, Delaney KM, Moorman AC, et al.. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338:853--860. MEDLINE | CrossRef
44. [44]Sulkowski MS, Mast EE, Seeff LB, Thomas DL. Hepatitis C virus infection as an opportunistic disease in persons infected with human immunodeficiency virus. Clin Infect Dis. 2000;30:S77--S84. CrossRef
45. [45]Thomas DL, Astemborski J, Rai RM, et al.. The natural history of hepatitis C virus infection: host, viral, and environmental factors. J Am Med Assoc. 2000;284:450--456. MEDLINE
46. [46]Piasecki BA, Lewis JD, Reddy KR, et al.. Influence of alcohol use, race, and viral coinfections on spontaneous HCV clearance in a US veteran population. Hepatology. 2004;40:892--899. MEDLINE | CrossRef
47. [47]Monga HK, Rodriguez-Barradas MC, Breaux K, et al.. Hepatitis C virus infection-related morbidity and mortality among patients with human immunodeficiency virus infection. Clin Infect Dis. 2001;33:240--247Epub 2001 Jun 2015. MEDLINE | CrossRef
48. [48]Graham CS, Baden LR, Yu E, et al.. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33:562--569Epub 2001 Jul 2006. MEDLINE | CrossRef
49. [49]Darby SC, Ewart DW, Giangrande PL, et al.. Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. UK Haemophilia Centre Directors' Organisation. Lancet. 1997;350:1425--1431. MEDLINE
50. [50]Eyster ME, Fried MW, Di Bisceglie AM, Goedert JJ. Increasing hepatitis C virus RNA levels in hemophiliacs: relationship to human immunodeficiency virus infection and liver disease. Multicenter Hemophilia Cohort Study. Blood. 1994;84:1020--1023. MEDLINE
51. [51]Eyster ME, Diamondstone LS, Lien JM, et al.. Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. The Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr. 1993;6:602--610. MEDLINE
52. [52]Lesens O, Deschenes M, Steben M, Belanger G, Tsoukas CM. Hepatitis C virus is related to progressive liver disease in human immunodeficiency virus-positive hemophiliacs and should be treated as an opportunistic infection. J Infect Dis. 1999;179:1254--1258. MEDLINE | CrossRef
53. [53]Ragni MV, Belle SH. Impact of human immunodeficiency virus infection on progression to end-stage liver disease in individuals with hemophilia and hepatitis C virus infection. J Infect Dis. 2001;183:1112--1115Epub 2001 Mar 1101. MEDLINE | CrossRef
54. [54]Soto B, Sanchez-Quijano A, Rodrigo L, et al.. Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis. J Hepatol. 1997;26:1--5. Abstract | Abstract + References | PDF (577 KB) | MEDLINE | CrossRef
55. [55]Garcia-Samaniego J, Rodriguez M, Berenguer J, et al.. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C. Am J Gastroenterol. 2001;96:179--183. MEDLINE | CrossRef
56. [56]Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35--S50.
57. [57]Puoti M, Bonacini M, Spinetti A, et al.. Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus. J Infect Dis. 2001;183:134--137Epub 2000 Nov 2016. MEDLINE | CrossRef
58. [58]Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected person. Ann Intern Med. 2003;138:197--207.
59. [59]Qurishi N, Kreuzberg C, Luchters G, et al.. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet. 2003;362:1708--1713.
60. [60]Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. J Am Med Assoc. 2002;288:199--206. MEDLINE
61. [61]Greub G, Ledergerber B, Battegay M, et al.. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet. 2000;356:1800--1805. MEDLINE
62. [62]Rockstroh JK, Spengler U. HIV and hepatitis C virus co-infection. Lancet Infect Dis. 2004;4:437--444.
63. [63]Laskus T, Radkowski M, Piasek A, et al.. Hepatitis C virus in lymphoid cells of patients coinfected with human immunodeficiency virus type 1: evidence of active replication in monocytes/macrophages and lymphocytes. J Infect Dis. 2000;181:442--448. MEDLINE | CrossRef
64. [64]Sherman KE, O'Brien J, Gutierrez AG, et al.. Quantitative evaluation of hepatitis C virus RNA in patients with concurrent human immunodeficiency virus infections. J Clin Microbiol. 1993;31:2679--2682. MEDLINE
65. [65]Lauer GM, Nguyen TN, Day CL, et al.. Human immunodeficiency virus type 1-hepatitis C virus coinfection: intraindividual comparison of cellular immune responses against two persistent viruses. J Virol. 2002;76:2817--2826. MEDLINE | CrossRef
66. [66]Kim AY, Lauer GM, Ouchi K, et al.. The magnitude and breadth of hepatitis C virus-specific CD8+ T cells depend on absolute CD4+ T cell count in HIV-1 coinfected individuals. Blood. 2004;30:30.
67. [67]Graham CS, Curry M, He Q, et al.. Comparison of HCV-specific intrahepatic CD4+ T cells in HIV/HCV versus HCV. Hepatology. 2004;40:125--132. MEDLINE | CrossRef
68. [68]Anthony DD, Yonkers NL, Post AB, et al.. Selective impairments in dendritic cell-associated function distinguish hepatitis C virus and HIV infection. J Immunol. 2004;172:4907--4916. MEDLINE
69. [69]Woitas RP, Rockstroh JK, Beier I, et al.. Antigen-specific cytokine response to hepatitis C virus core epitopes in HIV/hepatitis C virus-coinfected patients. AIDS. 1999;13:1313--1322. MEDLINE
70. [70]Mehta SH, Cox A, Hoover DR, et al.. Protection against persistence of hepatitis C. Lancet. 2002;359:1478--1483. MEDLINE
71. [71]Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology. 1999;29:908--914. MEDLINE | CrossRef
72. [72]Vento S, Garofano T, Renzini C, et al.. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med. 1998;338:286--290. MEDLINE | CrossRef
73. [73]Poynard T, Marcellin P, Lee SS, et al.. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet. 1998;352:1426--1432. MEDLINE
74. [74]Mauss S, Klinker H, Ulmer A, et al.. Response to treatment of chronic hepatitis C with interferon alpha in patients infected with HIV-1 is associated with higher CD4+ cell count. Infection. 1998;26:16--19. MEDLINE
75. [75]Soriano V, Garcia-Samaniego J, Bravo R, et al.. Interferon alpha for the treatment of chronic hepatitis C in patients infected with human immunodeficiency virus. Hepatitis-HIV Spanish Study Group. Clin Infect Dis. 1996;23:585--591. MEDLINE
76. [76]Sterling RK, Sulkowski MS. Hepatitis C virus in the setting of HIV or hepatitis B virus coinfection. Semin Liver Dis. 2004;24:61--68. CrossRef
77. [77]Brau N, Rodriguez-Torres M, Prokupek D, et al.. Treatment of chronic hepatitis C in HIV/HCV-coinfection with interferon alpha-2b+ full-course vs. 16-week delayed ribavirin. Hepatology. 2004;39:989--998. MEDLINE | CrossRef
78. [78]Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al.. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351:438--450. CrossRef
79. [79]Chung RT, Andersen J, Volberding P, et al.. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004;351:451--459. CrossRef
80. [80]Carrat F, Bani-Sadr F, Pol S, et al.. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. J Am Med Assoc. 2004;292:2839--2848. CrossRef
81. [81]Laguno M, Murillas J, Blanco JL, et al.. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS. 2004;18:F27--F36.
82. [82]Pawlotsky JM. Treating hepatitis C in difficult-to-treat patients. N Engl J Med. 2004;351:422--423. CrossRef
83. [83]Norris S, Taylor C, Muiesan P, et al.. Outcomes of liver transplantation in HIV-infected individuals: the impact of HCV and HBV infection. Liver Transpl. 2004;10:1271--1278.
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